This study demonstrated that DA and its oxidative metabolites: H2O2 and aminochrome (AM), cyclized DA quinones, could all directly inhibit proteasome activity. DA and AM, especially AM, could induce intensive and irreversible proteasome inhibition, whereas proteasome inhibition induced by H2O2 was weaker and GSH reversible. It was concluded that DA induced irreversible proteasome inhibition via DA-derived quinones, rather than through small molecular weight ROS. The AM was also more toxic than H2 O2 to dopaminergic MN9D cells. Furthermore the cytotoxicity and proteasome inhibition induced by DA, AM and H2 O2 could be abrogated by GSH, ascorbic acid (AA), Vitamin E, SOD (superoxidase dismutase) or CAT (catalase) with different profiles. Only GSH was potent to abrogate DA, AM or H2O2 -induced cell toxicity and proteasome inhibition, as well as to reverse H2O2-induced proteosome inhibition. Therefore, therapeutic strategies to increase GSH level or to use GSH substitutes should function to control PD onset and development.